2-Azacycloalkylmethyl substituted benzhydryl ketones and carbinols

ABSTRACT

Novel derivatives of 2-azacycloalkylmethyl substituted benzhydryl ketones and carbinols are described which are useful as anticoagulants.

United States Patent [1 1 Grisar et a].

[ Mar. 11, 1975 Z-AZACYCLOALKYLMETHYL SUBSTITUTED BENZHYDRYL KETONES AND CARBINOLS [75] Inventors: J. Martin Grisar; George P.

Claxton, both of Cincinnati, Ohio [73] Assignee: Richardson-Merrell Inc., New York.

[22] Filed: Apr. 25, 1973 [21] App]. No.1 354,315

[52} U.S. (I 260/293.8., 260/239 B, 260/293.5|,

zen/293.73, 260/2938}, 2.60/29384,

260/296 R, 260/296 D. 260/3265 R,-

[56] References Cited UNITED STATES PATENTS 3.316.272 4/1967 Roberts ct all. IMO/293.84 3,783,162 l/l974 Grisur ct ul. 260/239 B OTHER PUBLICATIONS J. Med. Chem. l5z500-503 (May 1972). Claxton et al.

Primary E.\uminer-Henry R. Jilcs Assistant E.\'uminerS. D. Winters Armrm'y, Agz'nl. or Firm-William J. Stein; George W. Rzluehl'uss, .lr.; Eugene 0. Roller [57] ABSTRACT Novel derivatives of 2-uzaeycloulkylmethyl substituted benzhydryl ketones and carbinols are described which are useful as anticoagulants.

5 Claims, N0 Drawings 1 Z-AZACYCLOALKYLMETHYL SUBSTITUTED BENZHYDRYL KETONES AND CARBINOLS FIELD OF THE INVENTION This invention relates to novel 2-azacycloalkylmethyl substituted benzhydryl ketones and their carbinol derivatives, to a novel method of their preparation and to their use in preventing the coagulation of blood.

BACKGROUND OF THE INVENTION This invention is related to copending application U5. Scr. No. 354,206, filed concurrently herewith, which describes a general method for the preparation of 2 nzacycliialkylmcthyl ketones. The closest prior art known to applicants includes the preparation of 4'- (fluoren-Q-ylidenemethyl)-2-(2- piperidyl)acetophenone, Claxton et al., J. Med. Chem. 15, 500 (1972), which is structurally unrelated to the instant compounds. To applicants knowledge, the compounds described and claimed herein are compounds which have not previously been described nor reported in literature.

SUMMARY OF THE INVENTION This invention relates to novel 2-azacycloalkylmethyl ketones and carbinols. More particularly, this invention relates to a class of substituted benzhydryl derivatives which are useful as anticoagulants and which may be represented by the generalformula:

wherein m is an integer of from l to 3; n is an integer of from 3 to 5; p is an integer of from 1 to 2; R is selected from the group consisting of hydrogen or lower alkyl having from I to 4 carbon atoms; R is selected from the group consisting of hydrogen and lower alkyl having from I to 4 carbon atoms; R is selected from the group consisting of hydrogen, lower alkyl having from I to 4 carbon atoms, lower alkoxy having from 1 to 4 carbon atoms, lower alkylthio having from 1 to 4 carbon atoms and halogen; Y is the radical =O or H radical =0 or and' the pharmaceutically acceptable acid addition salts thereof.

The compounds of the present invention are prepared by heating a solution of a l-phenyll(substituted)phenyLZ-propanone or a l-lower alkyl- 1 -phenyl-l (substituted) phenyl-2-propanone with magnesium methyl carbonate to form a magnesium chelate and condensing this chelate solution with a l-azacycloalkene in an atmosphere of carbon dioxide. The 2-azacycloalkylmethyl substituted benzhydryl ketones so prepared are readily reduced to their corresponding alcohol by means of sodium borohydride.

A variety of compositions are also included within the scope of the present invention which are useful as anticoagulants.

DETAILED DESCRIPTION OF THE INVENTION As seen by an examination of formula 1) above, the

compounds of the present invention share in common a 2-azacycloalkylmethyl moiety and a benzhydryl or substituted benzhydryl moiety attached to the keto or carbinol function of the molecule. The various azacycloalkylmethyl moieties include the 5, 6 and '7- membered nitrogen-containing saturated heterocyclic rings as defined by the symbol n. Thus, when n is an integer of from 3 to 5 and R is hydrogen, the corresponding heterocycles: l-pyrrolidine, piperdinc and 2.- 3,4,5,6,7-hexahydro-lH-azapine are delineated. Such heterocycles may be further substituted as illustrated by the symbol R which represents a lower alkyl group in additin to hydrogen. The term lower alkyl includes members having from 1 to 4 carbon atoms. Illustrative members of this group include the radicals methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl and t-butyl. The 2-azacycloalkyl rings may be either mono or disubstituted as indicated by the symbol p. When disubstituted, the lower alkyl radicals may be substituted either upon the same carbon atom or upon different carbon atoms. Further substitution in the 2-position, however, is precluded as illustrated by the presence of a hydrogen atom in Formula (1) above. Thus, for example, 6-methyl-2,3,4,5-tetrahydropyridine and Z-phenyl-l-pyrroline were found not to undergo condensation.

The presence ofa benzhydryl or substituted benzhydryl moiety is also shared in common as to all of the novel compounds described herein. This terminal portion of the molecule, which can also be regarded as a (substituted) diphenylmethyl radical, is also joined to the keto or carbinol function. The methyl group which bears both phenyl radicals may be further substituted with a lower alkyl radical as indicated by the symbol R in formula (1) above. The expression lower alkyl as used with regard to the symbol R includes the same members as previously enumerated for the symbol R The bennzhydryl moiety may be substituted or unsubstituted as indicated by the symbol R Additionally, the phenyl ring may be either mono, di or trisubstituted as indicated by the symbol m. When this ring is multisubstituted, i.e., the symbol m is an integer of from 2 to 3, the phenyl radical can be indifferently substituted. That is to say, all of the substituents on the phenyl ring need not be the same. Substitution can occur at any one of the available positions of the phenyl ring as indicated by the non-specific attachment of the R bond to the center of said ring. The symbol R includes substituents which are in the nature of aliphatic radicals, aliphatic ethers and aliphatic thioethers. In each instance, the apliphatic substituent is a lower alkyl group having from 1 to 4 carbon atoms, represented by the same previously enumerated for thhe radical R The phenyl radical may also be substituted with one, two or three halogen atoms. The term halogen" refers only to the fluoro, chloro and bromo radicals.

The novel process described herein results in the preparation of 2-azacycloalkylmethyl substituted benzhydryl ketones. Reduction of these ketones to the corresponding alcohols, which are also active anticoagulants, is readily achieved using methods well known to those skilled in the art. Suitable reducing agents inganic acids which form suitable salts include the mono. elude complex metal hydride reducl g ag n PP di and tricarboxylic acids. Illustrative of such acids are. c have foufldsodlum bofcfhydnde to be the f for example, acetic, propionic, glycolic, lactic, pyruvic, g agent of Cholce y g out the reduction of malonic, succinic, glutaric, fumaric, malic, tartaric, citthese ketones. Two or more moles of sodium borohy- 5 i ascorbic, maleic, hydroxymalic, benzoic, dride f g y usedPer l of ketone fe'duced, hydroxybenzoic, phenylacetie, cinnamic, salicylic, 2- the additional bOIOhydlldB serving to neutralize the phenoxybehzoie and lf i acids Such as methahesuh Salts of the 2"azacydoalkylmethylSubstlmted t y i' fonic acid and Z-hydroxyethanesulfonic acid. Either ryl ketones to their free base forms. The reaction IS h mono or h dh id Salts can b f d, d h conducted in various organic solvents such as metha l0 Salts can be i i in either a hy Or a Substannol, tetrahydrofuran or ethyl ether for period ranging i ll anhydrous form,

from a few minutes to about 24 hours. In general, the I general h zlo lkyl ethyl ub tituted reactants are mixed together at temperatures of 0C. or b h ketones f the present invention are below, whereupon the temperature IS gradually allowed pared by reacting a Substituted benzhydryl methy] to increase to 30C. Upon completion of the reaction, tone with magnesium methyl Carbonate (MMC) in the reaCti n m x e is treated With Watfif and the lution to form a magnesium chelate. The resulting chezazacycloalkylmethyl Substituted Vinylene carbinols late is condensed in an atmosphere of carbon dioxide are isolated and further purified by crystallization from i a p lk h or a Substituted 1- an appropriate Organi Solvent azacycloalkene at moderate or ambient temperatures.

The Subclass of 'p p y y Substituted benz' The 2-azacycloalkylmethyl substituted benzhydryl kehydryl ketones are of Particular interest inasmuch as tones which are formed are isolated as their acid addiy I 8 anticoagulant activity and are readily tion salts or as their free base by precipitation or exprcparcd by condensa ion f the magnesium chelate traction from the reaction mixture. This reaction is with the trimcr of 2,3,4,5tetrahydropyridine. This schematically represented as f n c-c-ci-l MMC we), c0 0 2 H\N7L(R1)P class of compounds is delineated in formula (1) above, wherein m, n, p, R,, R and R have the values previwhere the symbol n is 4, R, is hydrogen, and Y is an oxo ously assigned.

group. The MMC reagent is prepared by the addition of Illustrative specific base eompouns which are encommagnesium turnings to dry methanol until all of the passed by formula (1) above, include: metal is converted to magnesium methoxide. A solvent l-phenyl-3-(2-piperidyl)- l -(p-tolyl)-2-propanone, 3,3- such as dimethylformamide is added and the stirred sodiphenyl-l-( z-pyrrolidinyl)-2 pentanone, 1,1- lution saturated with dry carbon dioxide as described diphenyl-3-[2-(hexahydro-lH-azepinyl)]-2- by H. L. Finkbeiner and M. Stiles, J. Am. Chem. Soc.,

propanone, l- (4-fluorophenyl)-l-phenyl-3-(2- 85, 616 (1963). When a methyl ketone is permitted to piperidyl)-2-propanone, l-(4-methylthiophenyl)-lreact with a large excess of this reagent, a chelate rephenyl-3-(5,5-dimethyl-2-pyrro|idinyl)-2-propanone, sults which is believed to have the formula:

l-(p-cumenyl l -phenyl 3-( 4-tert.-butyl-2- M piperidinyl)-2-propanone, 3,3-diphenyl-l-[2- (hexahydrol H-azepinyl )]-2-butanone, 3-(2,4-

dichlorophenyl )-3-phenyll -(2-piperidyl)-2- R C O heptanone, l,l-diphenyl-3-(5-methyl-2-pyrrolidinyl)- 2-propanone, 3,3-diphenyl-l-(2-piperidyl)-2- butanone, a-(a-methyl-a-phenylbenzyl)-2- V) piperidineethanol, a-(a-ethyl-a-phenylbenzyl)-2- Generally, a 2 to 6 molar excess of the MMC reagent pyrrolidineethanol, 2-(2,5-dimethyl-a-phenylbenzyl)- is employed at a temperature ranging from to 2-piperidineethanol, and a-(diphenylmethyl)-2- C. Preferably an excess of 4 moles of MMC rea- (hexahydro-lH-azepine)ethanol. gent is used for chelation at the higher temperatures. The expression pharmaceutically acceptable acid The methanol that is formed is removed by sweeping a addition salts refers to any non-toxic organic or inorstream of an inert gas, such as nitrogen, over the hot soganic acid addition salts of the base compounds repre- 65 lution. After a period of time ranging from 2 to 36 sented by Formula (I). Illustrative inorganic acids hours the chelate solution is permitted to cool and the whi h f rm suita le sa t in ud hy hl hydroinert gas is replaced with carbon dioxide. The solution bromic, sulfuric and phosphoric acids as well as acid is saturated with carbon dioxide and a carbon dioxide metal salts such as sodium monohydrogen orthophosatmosphere is maintained throughoutt the condensaphate and potassium hydrogen sulfate. Illustrative ortion of the chelate with the l-azaeycloalkene.

To the magnesium chelated methyl ketone solution is added a one molar equivalent or slight excess of lazacycloalkcne with stirring. In general the condensation is effected by stirring the reaction mixture at ambient temperatures, The preferred reaction solvent is dimethylformamide since the MMC reagent is ordinarily prepared therein. On occasion it may be advantageous to add an additional inert solvent to the reaction mixture if, for example, the reaction is to be conducted at a temperature of less than -6 1 C., the freezing point of dimcthylformamide. It is further practicable to precipitate the magnesium chelate by the addition of large amounts of ether and to dissolve or suspend the precipitated chelate in other inert solvents. Suitable solvents include tetrahydrofuran, benzene or dimethylacetamide.

Condensation takes place at temperatures ranging from -50 to lC. Preferably the reaction is conducted at temperatures ranging from 0 to 60C. both as a matter of convenience and since elevation of the reaction temperature above 100C. results in diminshed yields.

The reaction time varies from a few hours to several weeks depending upon the reaction temperature and the nature of the reactants, particularly with respect to the degree of steric hindrance of the substituted benzhydryl methyl ketone (II). Inasmuch as the reaction is conducted and remains a homogenous solution until completion, the duration of the reaction can readily be extended for several weeks. Preferably the reaction is conducted in a period of from l6 to 60 hours.

Of particular importance to the successful operation of this reaction is the maintenance of an appropriate atmosphere. Some success is obtained under normal atmospheric conditions. particularly in the presence of a small amount of moisture. Under anhydrous conditions in an atmosphere of nitrogen, however, no product is obtained. Consistently good yields result when the condensation is carried out in an atmosphere of carbon dioxide.

vents or solvent mixtures.

It is important to note that the l-azacycloalkenes can exist as trimers, as for example, the trimers of lpyrroline and 2,3,4,5-tetrahydropyridine. In the case of the latter compound it can exist in two isomeric forms that are known as a and B-tripiperidein. In solution these trimers readily depolymerize to their monomers in a manner similar to the well known behavoir of for maldehyde. However, under alkaline aqueous conditions 2,3,4,5-tetrahydropyridine undergoes an irreversible self-condensation to form 'y-tripiperidein. This self-condensation does not occur using the process of the present invention.

Illustrative l-azacycloalkenes as indicated in Formula (III) above which are useful in the instant process include: l-pyrroline, 3-methyl-l-pyrroline, 5,5-dimethyl-l-pyrroline, 3-propyl-2,3,4,5 tetrahydropyridine, 4-t.-butyl-2,3,4,5- tetrahydropyridine, 3,5-dicthyl-2,3,4,5- tetrahydropyridine, 3,4,5,6-tetrahydro-2H-azcpine, and 2,2-dimethyl-3,4,5,o-tetrahydro-2H-azepine.

The l-phenyl-l-(substituted)phenyl-Z-propanones employed herein as starting materials are prepared by a Friedel-Crafts alkylation with 3-bromo-3- phenylpropan-Z-one, cf., R. C. Fuson et al., J. Amer. Chem. Soc. 67, 386 (I945).

s) a m ii BI! fi CH-C-CHa CH-C-CH The l-lower alkyl-l-phenyl-l-(substituted)phenyl-2- propanones are prepared by a Grignard reaction upon the corresponding nitriles 2 (1) sMQ I23 C-CN C'CCHS (2) HCl The desired products of this invention are isolated by pouring the reaction mixture into an excess of dilute acid. Preferably a mixture of2 to 12 normal hydrochloric acid and ice is employed. When the acid addition salt of the desired 2-azacycloalkylmethyl ketone precipitates, it is collected by filtration. Alternatively, the acidified reaction mixture is extracted with a suitable solvent, as for example, chloroform or methylene chloride, and the solvent extract evaporated, leaving the desired product as a residue. It is also possible, but generally more cumbersome, to treat the acidified reaction mixture with a base such as sodium hydroxide until alkaline. The desired product can then be extracted using The compounds of the present invention, including their acid addition salts and isomers, are useful as anticoagulants. They affect the coagulation of blood by preventing the aggregation of blood platelets. The blood platelets play a dominant role in thrombotic conditions, both in the initial event and at the occlusive stage. Arterial thrombosis, particularly in arteries supplying the heart muscle .and brain, is a leading cause of death and disability. The compounds of the present invention can be administered to animals, mammals and humans, either per se or in combination with conventional pharmaceutical carriers in dosage unit forms. Suitable dosage unit forms include oral preparations an appropriate solvent from the alkaline slurry containsuch as tablets, capsules, powders, granules, oral soluing precipitated magnesium hydroxide. In either event the crude products are readily purified by recrystallization of their acid addition salts using ordinary soltions and suspensions, sublingual and intrabuccal preparations, as well as parenteral dosage unit forms which are useful for subcutaneous, intramuscular or intravenous administration. The quantity of active ingredient administered can vary over a wide range so as to provide from about 1.0 mg/kg to about 100 mg/kg of body weight per day in order to achieve the desired effect. Each unit dose can contain from about to 500 mg of the active ingredient in combination with the pharmaceutical carrier. Such doses may be administered from 1 to 4 times daily.

In preparing solid compositions such as tablets, the principal active ingredient is mixed with conventional pharmaceutical excipients such as gelatin, starches, lactose, magnesium stearate, talc, acacia, dicalcium phosphate and functionally similar materials. Tablets can be laminated, coated or otherwise compounded to provide for a prolonged or delayed action and to release a predetermined successive amount of medication. Capsules are prepared by mixing the active ingredient with an inert pharmaceutical filler or diluent and filled in either hard gelatin capsules or machine encapsulated soft gelatin capsules. Syrups or elixirs can contain the active ingredients together with sucrose or other sweetening agents, methyl and propyl parabens as preservatives, and suitable coloring and flavoring agents.

Parenteral fluid dosage forms are prepared by utiliz ing the active ingredient in a sterile liquid vehicle, the preferred vehicle being water or a saline solution. Compositions having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from about 0.1 mg to about 3 grams of the active ingredient in a' vehicle consisting of a mixture of nonvolatile liquid polyethylene glycols which are soluble in both water and organic liquids, and which have molecular weights ranging from about 200 to about 1500. Such solutions may advantageously contain suspending agents, such as sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or polyvinyl alcohol. Additionally, they may contain bactericidal and fungicidal agents, as for example, parabens, benzyl alcohol, phenol or thimerosal. If desired, isotonic agents can be included, such as sugar or sodium chloride, as well as local anesthetics, stabilizing or buffering agents. In order to further enhance stability, the parenteral compositions may be frozen after filling and water removed by freezedrying techniques well known in the art, enabling such dry, lyophilized powders to be reconstituted immediately prior to their use.

The following preparations and examples are illustrative of the novel compounds of the present invention and their compositions, but are not to be construed as necessarily limiting the scope thereof.

EXAMPLE I 2,3,4.5'Tetrahydropyridine Trimer To 170 g (2.0 moles) of piperidine is added 120 g (2.0 moles) of acetic acid via dropwise addition at a temperature below C. The resulting solution is added dropwise over a period of one hour to an aqueous solution containing 2.2 moles of Ca(ClO) while maintaining the temperature of the reaction mixture at 0 to 5C. Stirring is continued for an additional minutes, and the mixture is extracted with ether. The ether extracts are combined, dried over anhydrous Na SO, and most of the solvent removed. (Caution! N- chloropiperidine tends to decompose spontaneously.) Approximately 200 ml of ether is permitted to remain and temperatures in excess of 60C. are avoided. The

remaining ether solution is added over a period of 2.5 hours in dropwise fashion to a vigorously stirred, re fluxing solution containing 265 g (4.0 moles) of potassium hydroxide in 1250 ml of anhydrous ethyl alcohol. Stirring is continued for 2 hours and the mixture is allowed to remain at room temperature during which the 2,3,4,5-tetrahydropyridine trimerizes. The potassium chloride which precipitates is removed by filtration, washed with anhydrous ethanol, and the ethanol removed from the filtrate by distillation. The residue is dissolved in 750 ml of water, the potassium chloride previously collected is added, and the solution extracted with ether. The combined ether extracts are dried (MgSOZ,) and the solvent removed by evaporation. Recrystallization of the residue from acetone yields 2,3,4,5-tetrahydropyridine as the a-trimer having a MP. of 586 1 C. The B-isomer (M.P. 4()-68C.) can be converted to the more stable a-isomer by recrystallizaton from acetone containing 2% water. The material so prepared is stored in a closed container over potassium hydroxide and is stable for over I year.

EXAMPLE ll l-Pyrroline Trimer To 140.3 g (1.05 moles) of N-chlorosuccinimide is added a solution of 71.1 g l mole) of pyrrolidine dissolved in l l of ethyl ether. The mixture is stirred at room temperature under N for 24 hours and sufficient water added to dissolve the solids. The ether phase is separated, dried over anhydrous sodium sulfate and the solvent evaporated under nitrogen. (Caution! N- chloropyrrolidine tends to decompose spontaneously.) Approximately ml of ether are permitted to remain and temperatures in excess of 60C. are avoided. The remaining ether solution is added over a period of l /2 hours in dropwise fashion to a vigorously stirred, icecooled solution of 2 N methanolic potassium hydroxide. Stirring is continued for 1 hour and the methanol removed at a temperature of 25-30C. at a reduced pressure of approximately 200 mm. Water is added to the remaining residue and the resulting mixture is subjected to continuous extraction with ethyl ether. The ether extract is separated and distilled under nitrogen at atmospheric pressure. Fractions having a B.P. 8l90C. and 9l97C. are collected, the latter fraction warming spontaneously, presumably due to exothermic trimerization. Both fractions are capable of.

condensation with MMC chelates of methyl ketones.

EXAMPLE lll l-Phenyll -(p-xylyl )propanone The following Example is illustrative of the preparation of l-phenyll substituted)phcnyl-2-propanones which are used as starting materials in the preparation of the compounds of the present invention.

To a solution of 67.] g (0.5 mole) of phenyl-2- propanone in l l of anhydrous ethyl ether, which is cooled in the water bath, is added via dropwise addition 79.9 g (0.5 mole) of bromine over a period of 60 minutes. The reaction mixture is stirred for 1 hour, transferred to a separatory funnel and washed with three separate portions of water. The ethereal solution is dried over anhydrous sodium sulfate and the solvent removed by evaporation. The residue which consists of 106 g of l-bromo-l-phenyl2-propanone is dissolved in ml of p-xylene and the solution is added to a suspension of 133 g (1 mole) of anhydrous aluminum chloride in 150 ml of p-xylene at 50-60C. via dropwise addition over a period of 90 minutes. The mixture is stirred for 30 minutes at 80C., allowed to cool over a period of 2 hours, and poured into a mixture of 2 N hydrochloric acid and ice. The organic layer is separated, washed with 2 N hydrochloric acid, followed by a 2 N sodium carbonate solution wash, and the organic layer is dried over anhydrous sodium sulfate. The solution is distilled at l 1 mm of pressure to remove the pxylene and the residue is further distilled at 1 mm of pressure. The fraction boiling at l59-63C., 82.5 g (69% yield), shows an infrared absorption at 1720 cm and has a nuclear magnetic resonance spectrum consistent with the structure of l-phenyl-l-(pxylyl)propanone.

EXAMPLE lV l,l-Diphenyl-3-( Z-piperidyl )propan-2-one Magnesium methyl carbonate (1.2 moles, 2 N in dimethylformamide) is heated to 120C. under an atmo sphere of carbon dioxide. The compound l,ldiphenylacetone, 63.0 g (0.3 moles), is added and the mixture is stirred at 120C. for a period of 4 hours under a stream of nitrogen to form the chelate, allowing the methyl alcohol that forms toescape. The mixture is cooled to room temperature under an atmosphere of carbon dioxide and 30.0 g (0.36 moles) of 2,3,4,5,-tetrahydropyridine (as a-tripiperidein) is added and stirring continued at room temperature for a period of 6 days under an atmosphere of carbon dioxide. The reaction mixture is poured into 375 ml of concentrated HCl on 400 g of ice and the resulting mixture is extracted with methylene dichloride. The extracts are combined, dried over anhydrous sodium sulfate and the solvent is removed. The crude oil is recrystallized twice from an aqueous isopropyl alcohol solution to yield l,l-diphenyl-3-(2-piperidyl)propan-2-one as the hydrochloride salt having a M.P. of l97-9C. (dec.)

when recrystallized from an aqueous isopropyl alcohol solution has a M.P. of l98-200C.

EXAMPLE Vl l-Phenyl-3-( 2-piperidyl l p-xylyl )-2-propanone Following essentially the same procedure as described in Example lV, but substituting l-phenyl-l-(pxylyl)-2-propanone for the l,l-diphenylacetone, results in the preparation of l-phenyl-3-(2-piperidyl)-l (p-xylyl)-2-propanone as the hydrochloride salt, which when recrystallized from an aqueous isopropyl alcohol solution has a M.P. of l90-2C.

EXAMPLE Vll l-(2,4,6-Trimethylphenyl l -phenyl-3-(2-piperidyl)-2- propanone Following essentially the same procedure as described in Example lV, but substituting l-(2,4,6- trimethylphenyl)-l-phenyl-2-propanone for the 1,1-

diphenylacetone above, results in the preparation of 1-(2,4,6-trimethylphenyl)-l-phenyl-3-(2-piperidyl)-2- propanone as the hydrochloride salt, which when recrystallized from an aqueous isopropanol solution. has a M.P. of 242-4C. (dec.)

EXAMPLE Vlll 3 ,3-Diphenyll 2-piperidyl )-2-hexanone Following essentially the same procedure as described in Example lV, but substituting 3,3-diphenyl-2- hexanone for the l,l-diphenylacetone above, results in the preparation of 3,3-diphenyll-(2-pipcridyl)-2- hexanone as the hydrochloride salt, which when recrystallized from an aqueous isopropyl alcohol solution. has a M.P. of l74-6C.

EXAMPLE lX l-(4-Chlorophenyl)-l-phenyl-3-(2-pipcridyl)-2 propanone Following essentially the same procedure as described in Example lV, but substituting l-(4- chlorophenyl)-l-phenyl-2propanone for the l,ldiphenylacetone above, results in the preparation of l-(4-chlorophenyl)-l-phenyl-3-(2-piperidyl)-2- propanone as the hydrochloride salt, which when recrystallized from an aqueous isopropanol solution has a M.P. of l9l3C.

EXAMPLE X a-( Diphenylmethyl )-2pipcridinecthanol glycolate To a suspension of 4.4 g (0.] 16 mole) of sodium borohydride in 250 ml of absolute ethanol is added with stirring 12.7 g (0.0386 mole) of l,l-diphenyl-3-(2- piperidyl)propan-Z-one hydrochloride. The mixture is stirred at room temperature overnight and poured into 1 l of water. The desired product is extracted into ether, and the combined ether extracts are treated with 3 portions of a l0% aqueous acetic acid solution. The acetic acid washes are combined, make alkaline with a 2 N sodium hydroxide solution and the desired product is re-extracted into ether. The glycolate salt is prepared by the addition of glycolic acid and recrystallized from isopropyl alcohol which contains a small amount of water. The product so obtained is a mixture of diastereoisomers which melts at l-87C. (dec.) Infrared, ultraviolet and nuclear magnetic resonance spectra all conform with the structure of a-(diphenylmethyD-Z- piperidineethanol glycolate.

Following essentially the same procedure but substituting for the 1,1-diphenyl-3-(2piperidyl)propan- 2-one hydrochloride above, the following ketone hydrochlorides: l-(2,4,6-trimethylphenyl l -phenyl-3-( 2- piperidyl)-2-propanone, 3,3-diphenyl-l -(2-pipcridy| 2-hexanone and l-( 4-chlorophenyl l -phenyl-3-( 2- piperidyl)-2-propanone results in the formation of the following carbinols as the glycolate salts, respectively: a-(2,4,6-trimethyl-a-phenylbenzyl)-2- piperidineethanol having a M.P. of 2l5-9C. (dec.), a-(a-phenyl-a-propylbenzyl)-2-piperidineethanol having a M.P. of l72-3C. (dec.) and a-(4-ch|oro-aphenylbenzyl)-2-piperidineethanol, the latter product having been obtained as two pairs of diastereoisomers, one pair having a M.P. of 176-80 C. (dec.) and the other pair being crystallized as a hemihydrate salt having a M.P. of 14952C. (dec.).

The anticoagulant activity of the compounds of this invention is determined by the inhibition of platelet (white thrombus) aggregation, which is the initial phase involved in the coagulation of blood. Plateletrich plasma (PRP) obtained from a human volunteer, having a platelet count of approximately 400,0OO/mm is aggregated using approximately 2 micrograms of adenosine diphosphate per ml of PRP. Quantitative platelet aggregation measurements are made using a photometer connected to an automatic recorder which measures the changes in optical clarity of standard cell containing the test solution. As the platelets aggregate, light transmission increases and thus both the rate of aggregation and the degree of aggregation can be determined. ln this fashion, adenosine diphosphate induccd aggregation of platelet-rich plasma is compared under identical circumstances to a corresponding aliquot containing a dilute solution of the test compound.

Following this procedure the compound l-phenyl-3- (2-piperidyl)- l p-xylyl 2-propanone hydrochloride at a concentration of 100 and 30 micrograms/milliliter demonstrates an in vitro inhibition of adenosine diphosphate induced platelet aggregation in human platelet-rich plasma of 91% and 28%, respectively.

EXAMPLE XII Preparation of a tablet formulation One thousand tablets for oral use, each containing 25 mg of 1-phenyl-3-(2-piperidyl)-l-(p-xylyl)-2- propanone hydrochloride are prepared according to the following formulation:

Grams (a) l-phenyl-3 (2-pipcridyl)-l- (p-xylyl)-2-propanone hydrochloride 25 (b) Dicalcium phosphate 150 (c) Mcthylcellulose, U.S.P. l5 cps) 6.5 (d) Talc (0) Calcium stearate 2.5

The l-phenyl-3-(2-piperidyl l p-xylyl )-2- propanone hydrochloride and dicalcium phosphate are mixed well, granulated with a 7.5% aqueous solution of methylcellulose, passed through a No. 8 screen and carefully dried. The dried granules are passed through a No. l2 screen, blended with talc and calcium stearate and compressed into tablets.

EXAMPLE Xlll Preparation of a capsule formulation One thousand two-piece hard gelatin capsules for oral use each containing 100 mg of 1-phenyl-3-(2- piperidyl)-l-(p-xylyl)-2-propanone hydrochloride are prepared from the following ingredients:

Grams (a) 1-phenyl 3'(2-piperidyl)-l-(p-xylyl)- 2-propanonc hydrochloride 100 (h) Lactose. U.S.P. 100 (0) Starch, U.S.P. 10 (d) Talc, U.S.P. 5 (e) Calcium stearate l EXAMPLE XlV Preparation of a parenteral solution 5 use is prepared from the following ingredients:

(irams Z-propanone hydrochloride 1 Polyethylene glycol 4000, U.S.P. 3 Sodium chloride 0.9 Polyoxyethylcnc derivatives of sorbitan monooleatc (TWEEN H0) U.S.P. Sodium metahisulfitc Methylparahen, U.S.P.

Propylparaben, U.S.P.

Water for injection q.s. to 100 ml (e) (f) (g) The parabens, sodium metabisulfite, and sodium chloride are dissolved in approximately one-half the volume of water forjnjection at C. with stirring. The solution is cooled to below 40C. and the active ingre dient is dissolved therein followed by the polyethylene glycol 4,000 and the polyoxyethylene derivatives of sorbitan monooleate. The cooled solution is adjusted to the final volume with water for injection and is then sterilized by sterile filtration through a suitable filter. Each one ml of solution contains 10 mg of l-phenyl-B- (2-piperidyl)-l-(p-xylyl)-2-propanone hydrochloride as the active ingredient.

We claim:

1. A 2-azacycloaklylmethyl substituted benzhydryl ketone and carbinol having the formula:

(CH2) l i c-c-cH2-cH j-(RQ \NH' wherein m is an integer of from 1 to 3; n is an integer of from 3 to 5; p is an integer of from I to 2; R is selected from the group consisting of hydrogen or lower alkyl having from 1 to 4 carbon atoms; R is selected from the group consisting of hydrogen and lower alkyl having from 1 to 4 carbon atoms; R:, is selected from the group consisting of hydrogen, lower alkyl having from i to 4 carbon atoms, lower alkoxy having from I to 4 carbon atoms, lower alkylthio having from 1 to 4 carbon atoms and halogen; Y is the radical =0 or or a pharmaceutically acceptable acid addition salt thereof.

2. A compound of claim 1 wherein n is 4; R is hydrogen; and Y is the radical q).

3. A compound of claim 1 which is l-phenyl-3-(2- piperidyl)-l-(p-xylyl)-2-propanone or a pharmaceutically acceptable acid addition salt thereof.

4. A compound of claim 1 which is 3,3-diphenyl-l- (2-piperidyl)-2-butanone or a pharmaceutically acceptable acid addition salt thereof.

5. A compound of claim I which is a-(u-phenyl-upropylbenzyl)-2-piperidineethanol or a pharmaceutically acceptable acid addition salt thereof. 

1. A 2-AZACYCLOALKYLMETHYL SUBSTITUTED BENZHYDRYL KETONE AND CARBINOL HAVING THE FORMULA:
 1. A 2-azacycloaklylmethyl substituted benzhydryl ketone and carbinol having the formula:
 2. A compound of claim 1 wherein n is 4; R1 is hydrogen; and Y is the radical O.
 3. A compound of claim 1 which is 1-phenyl-3-(2-piperidyl)-1-(p-xylyl)-2-propanone or a pharmaceutically acceptable acid addition salt thereof.
 4. A compound of claim 1 which is 3,3-diphenyl-1-1-(2-piperidyl)-2-butanone or a pharmaceutically acceptable acid addition salt thereof. 